This invention relates to novel, therapeutically useful polypeptides which exhibit varying degrees of phagocytosis or pinocytosis stimulation in mammals, including humans. It relates also to pharmaceutical compositions containing such polypeptides as well as to their use in mammalian patients in need of such stimulation or inhibition.
The gamma globulin fraction of whole mammalian blood is the fraction which contains the antibodies utilized by the body in resisting invasion by antigens. More specifically, the gamma globulin fraction of mammalian blood is the fraction containing substances which the body utilizes in combatting attack by infectious diseases. The production of antibodies is a natural defense mechanism of the body stimulated by the presence of antigens in the body. Normally specific antibodies are produced to combat specific antigens and, in many instances, the body thereafter maintains an antibody level against the specific antigen or infectious organism so that reinfection is inhibited and often prevented.
The use of the gamma globulin fraction of whole mammalian blood as a therapeutic agent has therefore attracted considerable medical attention since it would seem possible to utilize this fraction from an individual who has successfully overcome an infection to stimulate resistance to that same infection in another individual.
Unfortunately, this approach to prophylaxis has not proved sufficiently fruitful and cannot be used on a long term basis except in cases of a gamma globulinemia. There are many reasons for this. One is that patients often reject gamma globulin, especially on repeated dosages because they treat the gamma globulin as an antigen and develop antibodies to reject it. Another is that an increase above the normal gamma globulin level in the blood may have untoward effects such as seen in hypergamma-globulinemia. Moreover, even in those instances where gamma globulin treatment can be employed, the treatment is not as effective as desired because the bulk of it tends to stay in the blood of the patients rather than diffuse into the tissues which is situs of infection.
It has been known for some time that a tetrapeptide L-threonyl-L-lysyl-L-propyl-L-arginine (tuftsin) has the ability to stimulate phagocytosis and subsequent destruction of bacteria by blood polymorphonuclear leucocytes especially neutrophilic leucocytes in mammals. It also stimulates pinocytosis to the same extent allowing the cells to obtain nourishment from the surrounding medium.
It has been discovered that tuftsin when administered to a patient initially degrades to a tripeptide lysyl-prolyl-arginine, and that this tripeptide acts as an inhibitor to the therapeutic action of tuftsin. Thus, if large amounts of tuftsin are administered, for example, parenterally a rather complex series of reactions takes place. One is the desired therapeutically useful reaction, another is the formation of the inhibitory tripeptide and the third is the inhibitory reaction. The rate of the last two reactions is, unfortunately, so high that the administration of higher doses of the therapeutic agent is counterproductive. As more is administered, more of the inhibitory tripeptide is produced and less of the tuftsin is available to fulfill its therapeutic purpose.